American Chemical Society
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Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer

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journal contribution
posted on 2008-07-24, 00:00 authored by Christopher D. Cox, Paul J. Coleman, Michael J. Breslin, David B. Whitman, Robert M. Garbaccio, Mark E. Fraley, Carolyn A. Buser, Eileen S. Walsh, Kelly Hamilton, Michael D. Schaber, Robert B. Lobell, Weikang Tao, Joseph P. Davide, Ronald E. Diehl, Marc T. Abrams, Vicki J. South, Hans E. Huber, Maricel Torrent, Thomayant Prueksaritanont, Chunze Li, Donald E. Slaughter, Elizabeth Mahan, Carmen Fernandez-Metzler, Youwei Yan, Lawrence C. Kuo, Nancy E. Kohl, George D. Hartman
Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor (11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that β-fluorination modulated the pKa of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound (14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.